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Haploinsufficiency of the lysosomal sialidase NEU1 results in a model of pleomorphic rhabdomyosarcoma in mice
Rhabdomyosarcoma, the most common pediatric sarcoma, has no effective treatment for the pleomorphic subtype. Still, what triggers transformation into this aggressive phenotype remains poorly understood. Here we used Ptch1(+/−)/ETV7(TG/+/−) mice with enhanced incidence of rhabdomyosarcoma to generate...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9489700/ https://www.ncbi.nlm.nih.gov/pubmed/36127469 http://dx.doi.org/10.1038/s42003-022-03968-8 |
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author | Machado, Eda R. van de Vlekkert, Diantha Sheppard, Heather S. Perry, Scott Downing, Susanna M. Laxton, Jonathan Ashmun, Richard Finkelstein, David B. Neale, Geoffrey A. Hu, Huimin Harwood, Frank C. Koo, Selene C. Grosveld, Gerard C. d’Azzo, Alessandra |
author_facet | Machado, Eda R. van de Vlekkert, Diantha Sheppard, Heather S. Perry, Scott Downing, Susanna M. Laxton, Jonathan Ashmun, Richard Finkelstein, David B. Neale, Geoffrey A. Hu, Huimin Harwood, Frank C. Koo, Selene C. Grosveld, Gerard C. d’Azzo, Alessandra |
author_sort | Machado, Eda R. |
collection | PubMed |
description | Rhabdomyosarcoma, the most common pediatric sarcoma, has no effective treatment for the pleomorphic subtype. Still, what triggers transformation into this aggressive phenotype remains poorly understood. Here we used Ptch1(+/−)/ETV7(TG/+/−) mice with enhanced incidence of rhabdomyosarcoma to generate a model of pleomorphic rhabdomyosarcoma driven by haploinsufficiency of the lysosomal sialidase neuraminidase 1. These tumors share mostly features of embryonal and some of alveolar rhabdomyosarcoma. Mechanistically, we show that the transforming pathway is increased lysosomal exocytosis downstream of reduced neuraminidase 1, exemplified by the redistribution of the lysosomal associated membrane protein 1 at the plasma membrane of tumor and stromal cells. Here we exploit this unique feature for single cell analysis and define heterogeneous populations of exocytic, only partially differentiated cells that force tumors to pleomorphism and promote a fibrotic microenvironment. These data together with the identification of an adipogenic signature shared by human rhabdomyosarcoma, and likely fueling the tumor’s metabolism, make this model of pleomorphic rhabdomyosarcoma ideal for diagnostic and therapeutic studies. |
format | Online Article Text |
id | pubmed-9489700 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-94897002022-09-22 Haploinsufficiency of the lysosomal sialidase NEU1 results in a model of pleomorphic rhabdomyosarcoma in mice Machado, Eda R. van de Vlekkert, Diantha Sheppard, Heather S. Perry, Scott Downing, Susanna M. Laxton, Jonathan Ashmun, Richard Finkelstein, David B. Neale, Geoffrey A. Hu, Huimin Harwood, Frank C. Koo, Selene C. Grosveld, Gerard C. d’Azzo, Alessandra Commun Biol Article Rhabdomyosarcoma, the most common pediatric sarcoma, has no effective treatment for the pleomorphic subtype. Still, what triggers transformation into this aggressive phenotype remains poorly understood. Here we used Ptch1(+/−)/ETV7(TG/+/−) mice with enhanced incidence of rhabdomyosarcoma to generate a model of pleomorphic rhabdomyosarcoma driven by haploinsufficiency of the lysosomal sialidase neuraminidase 1. These tumors share mostly features of embryonal and some of alveolar rhabdomyosarcoma. Mechanistically, we show that the transforming pathway is increased lysosomal exocytosis downstream of reduced neuraminidase 1, exemplified by the redistribution of the lysosomal associated membrane protein 1 at the plasma membrane of tumor and stromal cells. Here we exploit this unique feature for single cell analysis and define heterogeneous populations of exocytic, only partially differentiated cells that force tumors to pleomorphism and promote a fibrotic microenvironment. These data together with the identification of an adipogenic signature shared by human rhabdomyosarcoma, and likely fueling the tumor’s metabolism, make this model of pleomorphic rhabdomyosarcoma ideal for diagnostic and therapeutic studies. Nature Publishing Group UK 2022-09-20 /pmc/articles/PMC9489700/ /pubmed/36127469 http://dx.doi.org/10.1038/s42003-022-03968-8 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Machado, Eda R. van de Vlekkert, Diantha Sheppard, Heather S. Perry, Scott Downing, Susanna M. Laxton, Jonathan Ashmun, Richard Finkelstein, David B. Neale, Geoffrey A. Hu, Huimin Harwood, Frank C. Koo, Selene C. Grosveld, Gerard C. d’Azzo, Alessandra Haploinsufficiency of the lysosomal sialidase NEU1 results in a model of pleomorphic rhabdomyosarcoma in mice |
title | Haploinsufficiency of the lysosomal sialidase NEU1 results in a model of pleomorphic rhabdomyosarcoma in mice |
title_full | Haploinsufficiency of the lysosomal sialidase NEU1 results in a model of pleomorphic rhabdomyosarcoma in mice |
title_fullStr | Haploinsufficiency of the lysosomal sialidase NEU1 results in a model of pleomorphic rhabdomyosarcoma in mice |
title_full_unstemmed | Haploinsufficiency of the lysosomal sialidase NEU1 results in a model of pleomorphic rhabdomyosarcoma in mice |
title_short | Haploinsufficiency of the lysosomal sialidase NEU1 results in a model of pleomorphic rhabdomyosarcoma in mice |
title_sort | haploinsufficiency of the lysosomal sialidase neu1 results in a model of pleomorphic rhabdomyosarcoma in mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9489700/ https://www.ncbi.nlm.nih.gov/pubmed/36127469 http://dx.doi.org/10.1038/s42003-022-03968-8 |
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